The role of luminal Ca regulation in Ca signaling refractoriness and cardiac arrhythmogenesis

Figure 1.. Shortened Ca-signaling refractoriness in cardiac disease. (A) Schematic illustration of a two-pulse protocol experiment showing the recovery of electrically stimulated Ca release is significantly delayed in relation to the recovery of electrical excitability. (B) Exponential constants (tau) of the recovery of Ca-transient amplitude ([Ca]cyt), free SR Ca ([Ca]SR), the amplitude of L-type Ca current (ICa), and peak of voltage-gated Na current (INa), are shown for control and diseased myocytes. Data for [Ca]cyt and [Ca]SR were obtained from the two-pulse experiments in ventricular myocytes from control and diseased hearts (Belevych et al., 2011, 2012). Rates of recovery for INa and INa were obtained with the Hund and Rudy (2004) model of the canine ventricular myocyte. Note the shortened time delay between the recovery of [Ca]cyt and [Ca]SR in diseased hearts.

Figure 2.. Mechanistic and molecular factors determining RyR2 refractoriness and its role in healthy cardiac function and arrhythmogenesis. RyR2 refractoriness is primarily determined by effects on RyR2 of luminal Ca, i.e., luminal deactivation, and modulated by other factors, including Ca-dependent inhibition of RyR2 by CaM, RyR2 phosphorylation and oxidation, and changes in SR Ca uptake. RyR2 refractoriness is essential for healthy cardiac relaxation and rhythm. Genetic and acquired defects in RyR2 complex result in shortened RyR2 refractoriness, synchronized aberrant Ca cycling, and arrhythmia.